Home       Objectives       Schedule       Lectures       Topics       Cases       Quizzes       PDA Refs     

Download for PDA

PERIPHERAL NEUROPATHY

Mark B. Bromberg, MD, PhD

OBJECTIVES

1)        Understand the anatomy and physiology of the peripheral nervous system.

2)         Understand the pathophysiology of axonal and demyelinating neuropathies and how electrodiagnostic studies can help distinguish between the two types.

3)         Recognize characteristic syndromes of peripheral neuropathies from the history

            and examination.

4)         Know major categories of peripheral neuropathies.

5)         Know treatment principles for major categories of peripheral neuropathies

INTRODUCTION

Peripheral neuropathies present as numbness and weakness and are common neurologic conditions.  However, not all complaints of numbness and weakness represent peripheral neuropathies, and it is important to have an understanding of the anatomy and physiology of the peripheral nervous system to accurately distinguish peripheral from central causes of numbness and weakness.  It is also helpful when evaluating a patient with a peripheral neuropathy to have in mind a schema or algorithm that is based on the physiology and pathology of nerves with the goal of accurately characterizing the neuropathy and making efficient use of diagnostic tests to yield an accurate diagnosis.

BASIC ANATOMY

The peripheral nervous system can be divided clinically into somatic nerves and visceral nerves.  Although the latter are the most numerous, most symptoms are referable to disorders of somatic nerves (Figure 1).

Somatic sensory nerves are myelinated fibers with cell bodies in the dorsal root ganglia.  Myelinated sensory fibers innervate cutaneous and deep receptors, and muscle receptors.  They include the fastest conducting fibers.

Somatic motor nerve fibers are also myelinated with cell bodies in the ventral horn of spinal cord and brain stem.  They innervate all skeletal muscles.  They include fast conducting fibers.

Visceral nerves are unmyelinated fibers that include a sensory component which innervates mostly nociceptors and a motor component that innervates vascular and smooth muscle and sweat glands.  These make up the major portion of the autonomic nervous system.  They conduct very slowly.

Schwann cells form the myelin wrapping around each myelinated axon.  Each myelin wrapping covers about 1 mm of axon, and Schwann cells with their myelin wrapping lie in series along axons.  The junctions between myelin wrappings are called nodes of Ranvier.  Schwann cells also cover unmyelinated axons, but do not form multiple wraps as they do for myelinated fibers.  Rather, for unmyelinated fibers, Schwann cells form a single cover over the unmyelinated fibers, and each Schwann cell invests several unmyelinated axons.

CLINICAL ANATOMY

Distribution: 

1) Most neuropathies affect both sensory and motor nerve fibers, and are called polyneuropathies.  However, there are examples of “motor only” and “sensory only” neuropathies.  For example, amyotrophic lateral sclerosis affects only motor nerves, and paraneoplastic sensory neuropathies affect only sensory nerves.  Autonomic nerve fibers are commonly involved in polyneuropathies, but rarely produce as many symptoms as do myelinated fibers.

2) Most polyneuropathies affect longer nerves first, causing early

disturbances in the lower extremities.  As the neuropathy progresses, there is a stocking pattern of sensory loss in the legs that may unroll to knee level, and later a glove pattern in the upper extremities that may unroll to elbow level (Figure 2).  There are also focal neuropathies, such as a median mononeuropathy at the wrist (carpal tunnel syndrome) or ulnar neuropathy (tardy ulnar palsy), or peroneal nerve at the knee (foot drop).

3) Because most polyneuropathies affect nerve (axon) or myelin function, a symmetric distribution of symptoms and signs is most common, although some asymmetry may be present early on.

Modality:

1) Sensory and motor nerves may be affected to equal degrees, but sensory nerve symptoms occur before motor nerve symptoms because sensory nerves do not possess the same type of compensatory mechanism of collateral sprouting as do motor nerves.  In collateral sprouting, terminal branches of surviving motor nerves sprout collateral nerves that innervate orphaned muscle fibers.  Collateral reinnervation preserves strength until there are insufficient numbers of remaining nerves, at which time weakness begins.

2) Furthermore, sensory nerves are "doubly" affected because they have both a peripheral and a central end, thus magnifying sensory dysfunction (Figure 1).                                

3) Symptoms can be divided into negative and positive types.  Negative sensory nerve symptoms include a lack of sensory perception (poor sensory discrimination, dead or heavy feeling) while positive symptoms include pain.  Negative motor nerve symptoms include weakness, and positive symptoms include fasciculations and cramps.

PHYSIOLOGY

Myelin serves as insulation, reducing current leakage along the axon.  At nodes of Ranvier, current leaks across the axon membrane, causing depolarization and regeneration of the action potential.  This results in jumping or saltatory conduction, which is fast (Figure 3).

Unmyelinated fibers allow current leakage across the axon membrane all along the axon.  This allows continuous conduction of depolarizing currents and the action potential is continuously regenerated and moves along the axon without jumps.  This mode of conduction is much slower.

For an axon to conduct a useful signal, it must be continuous or intact from one end to the other.  For a sensory fiber, this is from the receptor to the spinal cord,  For a motor fibers, this is from the spinal cord to the muscle.

PATHOPHYSIOLOGY

Neuropathies involve damage to the axon or to myelin, or to both.  It is worthwhile reviewing the changes that occur with damage to each element.

Primary demyelination slows or halts nerve conduction (Figure 3).  Individual Schwann cells lose their myelin from the underlying pathologic process.  The loss may be spotty; with each Schwann cell covering about 1 mm of axonal length, there are many sites for damage along a nerve fiber.  If a few Schwann cells lose their myelin, conduction slows, but if too many consecutive Schwann cells lose their myelin, conduction slows to a halt (Figure 4).  A whole nerve may contain several thousand nerve fibers.  Therefore, impulse conduction along individual fibers may be unaffected, may be mildly slowed, or blocked.  The longer the nerve segment, the greater chance of detecting mild degrees of slowing.

Primary axonal damage reduces the number of fibers in the nerve.  This usually affects the distal ends of the nerve.  As a consequence, the nerve is disconnected from the receptor for sensory fibers, or from the muscle for motor fibers.  This results in fewer impulses conducted along a nerve, centrally for sensory fibers or peripherally for motor fibers (Figure 4). 

CLINICAL EVALUATION OF PERIPHERAL NEUROPATHY

            As for all neurologic cases, the diagnosis is obtained mostly from the history, and confirmed by the examination.  The role of diagnostic tests is to help define the underlying pathology.

            The first step in diagnosing a peripheral neuropathy is to exclude central nervous system causes.  Although focal symptoms may result from damage to single nerves or nerve roots, consideration must also be given to strokes and mass occupying lesions.  For example, marked weakness and numbness of the legs with no involvement of the arms raises the question of a myelopathy.  Time course is important.  Peripheral neuropathies almost always have a chronic course, measured in months, and rarely in weeks.  Strokes, on the other hand, occur suddenly or within hours. 

            In general, peripheral neuropathies start insidiously in the longest nerves with symptoms of numbness and deadness in the feet or ankles.  Pain may or may not be a symptom.  Weakness will be noted later because of collateral reinnervation.  When sensory symptoms have advanced up the leg to just below the knee, shorter nerves are involved and similar symptoms will appear in the hands.  In severe and advanced neuropathies, when symptoms reach the elbows, sensory abnormalities will be noted in the front of the abdomen (Figure 2).

CLINICAL TESTING

It is advantageous to make clinical testing objective to help identify true nerve abnormalities.  It is also useful to make sensory testing semiquantitative to help follow the clinical course.

Motor testing:

1) Posture: The carrying angle at the ankle (between the tibia and dorsum of the foot) is normally about 120 degrees.  A greater angle, 150 to 180 degrees, suggests distal weakness (hypotonia) and a polyneuropathy.

2) Atrophy: Useful muscles to assess bulk in the legs include the extensor digitorum brevis muscle on top of the foot, and the first dorsal interosseous muscle in the hand.

3) Strength: Focus on testing distal muscles because they will be weaker than proximal muscles.  In the legs, strength of the extensor hallucis longest (great toe extension), extensor digitorum brevis (lesser toe extension), and toe flexors are suitable.  Compare heel elevation (toe walking) to toe elevation (heel walking) during walking, because toe elevation will be affected earlier than heel elevation (anterior tibialis muscle more vulnerable than gastrocnemius).  In the arms, strength of finger abduction, thumb abduction, and finger extension are suitable.  Proximal weakness in addition to distal weakness is rare in polyneuropathies, but is an important finding and suggests specific types of polyneuropathy (inflammatory polyradiculoneuropathy).

4) Strength scale: Use the qualitative MRC scale, but quantitative measurement with a grip dynamometer is also very useful.  The MRC scale (Medical Research Council of the UK) was developed in the 1940’s primarily as an aid to charting the return of strength after war-related peripheral nerve injuries.  Scale: 0 = no muscle movement; 1 = flicker of muscle movement; 2 = trace movement but not able to fully overcome gravity; 3 = just able to overcome gravity; 4 = weak; 5 = full strength.  As you can see, most clinical weakness is between grades 4 and 5.  The scale has been supplemented with + and - (ie, 4-, 4+, 5-).  Although somewhat subjective, with careful thought, the scale is reproducible.

Sensory testing:

1) Principles: look for clear abnormalities that are consistent with the underlying pathology (sensory loss in stocking and glove or single nerve distribution); use forced choice testing ("feels more normal, less normal, or no difference"). 

2) Light touch: compare distal (stocking or glove) to proximal sites (normal); eg, hand to face, foot to hand.

3) Vibration: use a128 Hz tuning fork; quantitate difference between patient and tester in number of seconds it takes for vibration to completely die out.

4) Sharp: distinguish sharp from dull end of a safety pin.

5) Coolness: round ends of tuning fork; compare distal to proximal sites.

6) Tendon reflexes: objective measure; if absent confirm by using reinforcement maneuvers.

ELECTRODIAGNOSTIC STUDIES

An electrodiagnostic study consists of assessment of nerve conduction and a needle EMG evaluation. 

Nerve conduction studies are carried out for sensory and motor nerves separately (Figure 5).  Major named nerves in the lower extremity (sural sensory and peroneal and tibial motor nerves) and upper extremity (ulnar and median motor and sensory nerves) are studied.  The nerves are activated with a brief electrical stimulus and the summed action potentials are recorded with electrodes over the sensory nerve or over the muscle.  Several measurements are made: the amplitude of the response is a measure of the number of axons, and the conduction velocity is a measure of the integrity of the myelin.  Conduction velocity can be assessed in three ways.  The distal latency is the time it takes impulses to go from the stimulating electrode to the recording electrode (not a true conduction velocity).  The conduction velocity between two points along the nerve is a true conduction velocity.  The F-wave latency is the time it takes for a nerve impulse to travel along a motor axon from the stimulation site to the alpha motor neuron and back (not a true conduction velocity, but assesses conduction over a long pathway-i.e., twice the motor nerve length).

The needle EMG examination can sample individual muscles and is the most sensitive test for denervation of muscle fibers.  Muscle fibers can be denervated by damage to motor nerves (neuropathy) or by damage to the muscle (myopathy).  Determination of which of the two pathologic processes is responsible can be made from the history and neurologic examination.

The basic electrodiagnostic findings that distinguish primary demyelinating from primary axonal neuropathies are the following.

Primary demyelination results in slowed or blocked conduction.

          Nerve conduction studies:

                        -distal amplitude greater than proximal

                        -abnormal temporal dispersion

                        -slow conduction velocity

                        -prolonged distal latency

                        -prolonged F-response latency

           EMG:  

                        -may be evidence of denervation

Primary axonal loss results in reduced amplitude but near normal conduction.

           Nerve conduction studies:

                        -distal and proximal amplitudes reduced nearly equally

                        -no abnormal temporal dispersion

                        -minimally slowed conduction velocity

                        -minimally prolonged distal latency

                        -minimally prolonged F-response latency

            EMG:              

                        -evidence of marked denervation

DIFFERENTIAL DIAGNOSIS

          Demyelinating-hereditary (non-acquired):

                        1) hereditary motor sensory neuropathy (HMSN) or Charcot-Marie-

                             Tooth - named after three neurologists (CMT)

                                    i) type I - slow conducting

                                    ii) type II - axonal type (nearly normal conduction velocity)

         Demyelinating-acquired:

                        1) acute inflammatory demyelinating polyradiculoneuropathy (AIDP or

                             Guillain-Barré syndrome)

                        2) chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)                                    3) chronic  

                             dysimmune polyneuropathy (subset of CIDP):

                                    i) monoclonal gammopathy of uncertain significance (MGUS)

                                    ii) osteosclerotic myeloma

                                    iii) multiple myeloma

                                    iv) Waldenstrom's macroglobulinemia

                                    v) Castleman's disease

                                    vi) other lymphoproliferative disorders

                                    vii) AIDS

                        3) diabetic polyneuropathy

                        4) multifocal demyelinating motor neuropathy with conduction block

                        5) other etiologies which may fulfill demyelination criteria

                                    i) arsenic polyneuropathy (acute stage)

                                    ii) amiodarone

           Axonal-acquired:

                        1) diabetic polyneuropathy

                        2) uremic polyneuropathy

                        3) acute intermittent porphyria

                        4) chronic and severe alcohol

                        5) amyloidosis

                        6) paraneoplastic

                        7) medications:

                                    i) nitrofurantoin

                                    ii) vincristine

                                    iii) cis-platinum

                                    iv) disulfiram

WORK UP AND EVALUATION

All neuropathies need electrodiagnostic testing to determine if the pathologic process is primary demyelinating, primary axonal, or mixed.

Hereditary neuropathies are probably more common than appreciated, and when the clinical and electrodiagonstic picture is suggestive, studying family members is valuable.  If a hereditary neuropathy is identified, there are genetic tests available to confirm the genotype for certain types.  The ability to genotype hereditary neuropathies is rapidly expanding.  When there is a clear diagnosis of a hereditary neuropathy, either by phenotype and family history or genotype, further work up and evaluation is not necessary.

Acquired primary demyelinating neuropathies are divided into acute (AIDP or the Guillain-Barré syndrome) and chronic (CIDP).  

          AIDP and CIDP require:

                        1) heavy metal screen when appropriate

                        2) examination of CSF protein

          CIDP requires additional studies:

                        1) serum immunofixation

                                    i) skeletal survey

                                    ii) marrow biopsy

           Primary axonal polyneuropathies require:

                        1) review medications

                        2) screen for diabetes, renal failure, vasculitis

TREATMENT

            Primary demyelinating polyneuropathies:

                        1) Treat underlying dysproteinemia if present 

                        2) AIDP-plasma exchange or intravenous immune globulin (IVIG)

                        3) CIDP-consider plasma exchange and prednisone or immunosuppressive agents

            Primary axonal polyneuropathies: 

                        1) Stop or change medication

                        2) Treat underlying disorder

EXAMPLES OF NEUROPATHIES

CASE NUMBER 1

History: A 65 year old gentleman comes to you with problems walking.  He can not feel his feet, they feel heavy or dead, as if he were walking on sticks.  He stubbed his toe but did not know of the injury until he noticed that his toe was swollen and black and blue.  He has IDDM, as did his mother.

Examination: He is a rotund man.  The pertinent findings are mild thinning of the intrinsic muscles of his hands and feet.  Strength is normal proximally in both arms and legs, but he had mild weakness of finger abduction, and no toe flexion or extension.  Deep tendon reflexes are trace in the arms, but absent in the legs.  He feels nothing to light touch at his feet, and describes mild differences on his hand compared to touching his face.  He indicates a line just below the knees, above which things feel normal.

Electrodiagnostic testing: There is no response to stimulating and recording from sensory nerves in his legs or arms.  There is no response to stimulating motor nerves and recording from muscles in the legs, but normal responses in the arms.  The needle EMG study showed neurogenic changes in muscles of his legs, worse in distal muscles, and mild changes in intrinsic hand muscles.

Diagnosis: diabetic polyneuropathy

1) Probably the most common neuropathy in the West.  Symptomatic neuropathy occurs in thirty percent of diabetics, and asymptomatic neuropathy occurs in over fifty percent.

2) Usually presents with negative symptoms of numbness and deadness in the feet and advances in stocking distribution and later in a glove distribution in the hands.  Feet may be insensate and unsuspected cuts may become infected.  Weakness may affect ambulation.

3) May also present with positive symptoms of intense burning at the feet, ankles, and shin.

4) There may be an associated autonomic neuropathy.

5) The pathology is primary axonal with secondary and milder demyelination.

6) The underlying pathophysiology is not clear.  There is no drug treatment that is effective in reversing the neuropathy although treatment trials are underway.  The best treatment is good glucose control.  For pain, only symptomatic treatment is available, and it may be hard to manage.

CASE NUMBER 2

History: A 38 year old woman makes an appointment because she can no longer wear shoes with high heels when she goes out.  Last year when she attended a wedding she had some problems dancing in dress shoes, but last month she kept twisting her ankles wearing the same pair of shoes.  She has always had trouble finding dress shoes to fit, and she is distressed because her mother had the same problems.

Examination: She has high arches and toes which look like the hammers of a piano.  Her legs are also very slender below the knee.  She has grade 4 weakness of ankle dorsiflexion, inversion and eversion, and she has difficulty walking on her heels.  Her deep tendon reflexes are trace at the knees and absent at the ankles.  She has poor perception of light touch across the top of her feet.

Electrodiagnostic testing:  She has no response to stimulating and recording from sensory nerves in the legs, and a very low and slow response in the arms.  Her motor slow conduction velocities are one quarter as fast as normal responses.  The needle examination showed minimal evidence for denervation in distal leg muscles.

Diagnosis: hereditary motor sensory neuropathy (HMSN) or Charcot-Marie-Tooth (CMT) neuropathy

1) More common than appreciated because of variable penetrance.  Since it is slowly progressive, affected family members may not appreciate involvement.

2) Usually presents with negative symptoms.  Distal leg and arm atrophy and high arches with hammer toes common.

3) Several types: type I involves primarily myelin and results in markedly slow conduction velocities; type II involves primarily axons and conduction velocities are unremarkable.

4) There is no known treatment.

CASE NUMBER 3

History: A 28 year old woman is in the emergency room because she has numbness of her legs and can not walk.  She was well until three days ago when she noted tingling in her lower legs.  During the day the tingling progressed in intensity and included her whole legs.  The next morning she had some unsteadiness of gait which progressed and she went to bed early.  This morning she did not have strength to stand from sitting on the edge of the bed and was too unsteady to walk.  She now has numbness in her hands.

Examination: She is anxious, but otherwise in no distress.  Her ability to close her eye and lips tightly is mildly impaired.  She can barely elevate her arms and had trace finger movements.  She can not elevate her legs and she can not walk even with support.  Her deep tendon reflexes are absent.  Sensory perception is markedly reduced in her feet and legs.

Electrodiagnostic testing:  There is no response to sensory nerve testing.  The response to motor nerve testing is of low amplitude and slow conduction velocity.  The needle EMG study shows no signs of denervation.

Diagnosis: inflammatory polyradiculoneuropathies

1) There are two types based on time course: acute inflammatory demyelinating polyradiculoneuropathy (AIDP) or the Guillain-Barré syndrome (GBS) is a monophasic illness reaching its nadir within four weeks.  Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) may follow several patterns of progression with a time course of months to years. 

2) Both types usually present with numbness and weakness of distal and proximal muscles.  This distribution of distal and proximal weakness can be explained by involvement of spinal roots which innervate both distal and proximal muscles as well as peripheral nerves.

3) Although both forms are similar in many respects, they likely have different pathophysiologic mechanisms.  Both involve demyelination and secondary axonal damage.

4) Treatment differs: plasma exchange for AIDP; plasma exchange and prednisone for CIDP.

CASE NUMBER 4

History: A 71 year old, previously active gentleman comes to you because he can no longer hold his golf club tightly, and has some difficulty walking up hills along the course.  He also notes cramping of his hand muscles when he grips the clubs tightly, and in calf muscles at night.  He has fallen several times and feels that his left leg is stiffer than his right and it will not do everything that he wants it to do.  He has lost 5 lbs, and his hand muscles are shrinking despite starting an exercise program (squeezing a tennis ball). 

Examination: Mild atrophy is noted in intrinsic hand muscles, right greater than left.  Diffuse fasciculations are also noted.  He had weak finger abduction, grade 4 on the right and 3+ on the left.  His left ankle dorsiflexion strength is weak on the left (grade 4) and there is a mild foot drop when walking.  His deep tendon reflexes were extraordinarily brisk with clonus at the ankles.  The sensory examination was normal.

Electrodiagnostic testing: Sensory nerve testing was normal.  Motor nerve testing showed normal conduction velocities but reduced response amplitudes in left hand and foot muscles.  The needle study showed evidence for denervation in all muscles tested, including those in the right arm and leg that had normal strength.

Diagnosis: motor neuron disease

1) The most common form in adults is amyotrophic lateral sclerosis (ALS). 

2) ALS involves the axons of motor nerves only, and sensory nerves are unaffected. 

3) This is a disease which starts asymmetrically

4) There is no known cure, but supportive care addressed to the particular problems of the patient is necessary.

FIGURE CAPTIONS:

Figure 1:  Clinical anatomy of the peripheral nervous system.  On left are visceral or unmyelinated fibers, both motor and sensory.  On right are somatic or myelinated fibers, both motor and sensory.  From: Schaumburg, Berger, Thomas: Disorders of Peripheral Nerves, Edition 2.  FA Davis, Philadelphia, 1992.

Figure 2:  Common distribution of symptoms in peripheral neuropathies.  On left is shown stocking-glove distribution.  On right is shown mononeuropathies (ulnar and peroneal nerves).  From: Schaumburg, Berger, Thomas: Disorders of Peripheral Nerves, Edition 2.  FA Davis, Philadelphia, 1992.

Figure 3:  Physiologic and pathophysiologic nerve conduction.  At top is normal saltatory conduction.  At bottom is blocked conduction in demyelinating neuropathy because ionic flow dies out (leaks across demyelinated segments) before reaching node of Ranvier.  From: Kandel, Schwartz, Jessell: Principles of Neural Science, Third Edition.  Elsevier, New York, 1991.

Figure 4:  Pathologic process.  At top is primary demyelinating neuropathy.  At bottom is primary axonal neuropathy.  From: Schaumburg, Berger, Thomas: Disorders of Peripheral Nerves, Edition 2.  FA Davis, Philadelphia, 1992.

Figure 5:  Methodology of nerve conduction studies.  In middle is limb showing median nerve with stimulating electrode sites.  Also shown is recording electrode sites for picking up motor nerve response from muscle.  At left is typical compound muscle action potential (CMAP).  At right is inset showing recording and stimulating sites for picking up sensory nerve response.  Also shown is inset with typical sensory nerve action potential (SNAP).  From: Oh: Clinical Electromyography. Nerve Conduction Studies, Edition 2.  Williams & Wilkins, Baltimore, 1993.

                                                   Home       Objectives       Schedule       Lectures       Topics       Cases       Quizzes       PDA Refs     

                                              Last updated:  10/05/2002                                                          © 2000-2002 John Rose, MD  University of Utah School of Medicine